A novel radical cyclization of 2-bromoindoles. Synthesis of hexahydropyrrolo[3,4-b]indoles

Article abstract of DOI:10.1039/b101859k

Hexahydropyrrolo[3,4-b]indoles 6, 10, and 13 are obtained from 2-bromo-3-carboxamides 5, 9, and 12, respectively, by a 1,5-radical translocation process followed by 5-endo-trig cyclization to the indole C-2 position.

Full text of DOI:10.1039/b101859k

A novel radical cyclization of 2-bromoindoles. Synthesis of
hexahydropyrrolo[3,4-b]indoles
Gordon W. Gribble,* Heidi L. Fraser and Jeanese C. Badenock
Department of Chemistry, Dartmouth College, Hanover, NH 03755-3564, USA.
E-mail: grib@dartmouth.edu
Received (in Corvallis, OR, USA) 16th February 2001, Accepted 14th March 2001
First published as an Advance Article on the web 17th April 2001
Hexahydropyrrolo[3,4-b]indoles 6, 10, and 13 are obtained
from 2-bromo-3-carboxamides 5, 9, and 12, respectively, by
a 1,5-radical translocation process followed by 5-endo-trig
cyclization to the indole C-2 position.
We wish to describe a new synthesis of hexahydropyrrolo[3,4-
b]indoles from 2-bromoindole-3-carboxamides involving se-
quential indole C-2 radical generation, 1,5-hydrogen atom
abstraction, and 5-endo-trig cyclization to the indole C-2
position. In connection with our interest in pyrrolo[3,4-
b]indoles1 and indolo[2,3-a]quinolizidines,2 we envisioned the
free radical sequence shown in Scheme 1 as an attractive route
to these ring systems.
Scheme 3 Reagents and conditions: i, Bu3SnH, AIBN, toluene, reflux, 36 h
(6, 54%; 4, 42%).
dihydroindole 6† (54%), along with the reduction product 4
(42%) (Scheme 3). The structure of 6 is fully supported by
spectral and analytical data, including an X-ray crystal structure
determination.5
We believe that this reaction involves the sequence (1)
generation of the expected C-2 radical, (2) 1,5-H atom
abstraction to give the a-amidoyl radical, (3) 5-endo-trig
cyclization to the indole double bond, and (4) hydrogen
abstraction to give indoline 6. The first two steps in this process
have been termed ‘radical translocation’ by Snieckus and
Curran.6 Attempts to improve the yield of 6 relative to reduction
product 4 using other radical generation methods have not been
successful. Treatment of indoline 6 with DDQ (CH2Cl2, rt) gave
indole 7 in 50% yield (Scheme 4).
Scheme 1
We herein report the viability of this sequence for the
synthesis of hexahydropyrrolo[3,4-b]indoles. The radical pre-
cursor 2-bromoindole 5 was prepared as shown in Scheme 2.
Indole (1) was converted to amide 3 in two steps as previously
described.3 Subsequent N-methylation and C-2 bromination
using the conditions described by Bergman4 for N-carboxy-
indole afforded 5† in excellent overall yield. An X-ray crystal
structure determination confirmed the structure of 5.5
Scheme 4 Reagents and conditions: DDQ, CH2Cl2, rt, 18 h (50%).
The radical cyclization was performed by the slow addition
over 36 h of a degassed solution of tri-n-butyltin hydride and
catalytic AIBN in toluene to a refluxing solution of bromo-
indole 5 in toluene. This resulted in the formation of the desired
As summarized in Scheme 5 we have applied this radical
cyclization to several other substrates (9, 12, 15) and two of
these afforded the expected cyclized pyrrolo[3,4-b]indoles 10
and 13. However, only reduction product 14 was obtained from
15.
Amides 8,† 11,† and 14,† were synthesized by N-methylation
of the corresponding indole-3-carboxamides3 in 97, 77, and
80% yields, respectively, as illustrated in Scheme 2 for 4. The
usual bromination procedure afforded the 2-bromoindoles 9,†
12,† and 15† in excellent yields. The structures of 9, 12, and 15
were confirmed by X-ray crystallography.5
Although radical cyclizations to the indole C-2 position are
precedented7 and the generation of indole C-2 radicals has been
described by Jones,8,9 our work is the first example of a
1,5-hydrogen atom transfer reaction of a 2-bromoindole-
3-carboxamide and subsequent 5-endo-trig cyclization to the
indole double bond. Following the completion of our initial
work, Jones reported9 a similar 1,5-H atom abstraction from the
radical derived from 2-bromo-3-formyl-N-(4-phenylbutyl)in-
dole and subsequent radical translocation and 5-exo-trig
cyclization to the indole C-2 position. Jones has also recently
described10 a radical translocation sequence leading to indole
C-3 5-exo-trig cyclization. Some other hydrogen atom abstrac-
Scheme 2 Reagents and conditions: i, (CF3CO)2O, Et2O, 0 °C (87%); ii,
BuLi, piperidine, THF, 0 °C (97%); iii, NaOH, EtOH, MeI, acetone, rt
(99%); iv, ButLi, THF, BrCl2CCCl2Br, 278 °C to rt (88%).
DOI: 10.1039/b101859k
Chem. Commun., 2001, 805–806
This journal is © The Royal Society of Chemistry 2001
805

1H, JA = 1.39 Hz, JB = 7.31 Hz), 7.46 (s, 1H), 7.19–7.35 (m, 3H), 3.81 (s,
3H), 3.06 (s, 3H), 1.57 (s, 9H); dC (CDCl3) 169.4, 136.8, 132.4, 126.1,
122.4, 121.2, 121.0, 114.4, 109.9, 56.4, 35.5, 33.4, 28.1; IR n(KBr)/cm21
3458, 3113, 2975, 1627 (Calc. for C15H20N2O: C, 73.74; H, 8.25; N, 11.47.
Found: C, 73.67; H, 8.30; N, 11.44%). 9: mp 105–106 °C; dH (300 MHz,
CDCl3) 7.57–7.71 (dt, 1H, JA = 1.2 Hz, JB = 8.0 Hz), 7.14–7.34 (m, 3H),
3.76 (s, 3H), 2.96 (s, 3H), 1.57 (s, 9H); dC (CDCl3) 167.1, 136.4, 125.8,
122.5, 121.0, 119.6, 114.7, 114.2, 109.5, 56.5, 34.2, 31.5, 28.0; IR n(film)/
cm21 3456, 3052, 2979, 1627 (Calc. for C15H19BrN2O: C, 55.74; H, 5.92;
N, 8.67; Br, 24.72. Found: C, 56.13; H, 5.94; N, 8.64; Br, 24.42%). 11: mp
111–112 °C; dH (300 MHz, CDCl3) 7.80–7.83 (dt, 1H, JA = 1.1 Hz, JB =
7.0 Hz), 7.13–7.28 (m, 4H), 3.70 (s, 3H), 3.63–3.67 (t, 4H, J = 5.9 Hz),
0
1.57–1.74 (m, 8H); dC (500 MHz, CDCl3, 245 C ) 166.9, 135.7, 129.8,
126.2, 121.8, 120.8, 120.1, 110.1, 109.3, 49.0, 45.6, 33.0, 29.3, 28.2, 27.2,
26.0; IR n(film)/cm21 3053, 2932, 1605 (Calc. for C16H20N2O: C, 74.97; H,
7.86; N, 10.93. Found: C, 74.90; H, 7.93; N, 10.79%). 12: mp 125–126 °C;
dH (300 MHz, CDCl3) 7.46 (d, 1H, JA = 7.1 Hz), 7.10–7.27 (m, 4H), 3.73
(s, 3H), 3.40–3.70 (m, 4H), 1.52–1.87 (m, 8H); dC (CDCl3) 166.0, 136.3,
125.6, 122.5, 120.8, 119.0, 113.0, 112.9, 109.5, 49.4, 45.9, 31.4, 29.5, 27.9,
27.4, 26.4; IR n(film)/cm21 3053, 2933, 1618; m/z 334 (M+), 255, 236
(100%), 130, 103, 77 (Calc. for C16H19BrN2O: C, 57.32; H, 5.71; N, 8.36;
Br, 23.83. Found: C, 57.57; H, 5.69; N, 8.35; Br, 23.54%). 14: mp 110–113
°C; dH (300 MHz, CDCl3) 8.15 (d, 1H, JA = 7.5 Hz), 7.38 (s, 1H), 7.34–7.21
(m, 3H), 3.81 (s, 3H), 3.69 (m, 2H), 1.95 (m, 2H); dC (500 MHz, CDCl3,
240 °C) 165.0, 135.9, 130.7, 127.0, 122.3, 121.8, 120.8, 110.2, 109.2, 48.9,
46.3, 33.3, 26.4, 24.2; IR n(film)/cm21 2942, 2872, 1590; m/z 228 (M+), 158
(100%), 130, 103, 77. 15: mp 100–105 °C; dH (300 MHz, CDCl3) 7.54 (d,
1H, J = 8.1 Hz), 7.29 (d, 1H, J = 8.3 Hz), 7.23 (td, 1H, JA = 7.6 Hz, JB =
1.0 Hz), 7.15 (td, 1H, JA = 7.6 Hz, JB = 1.2 Hz), 3.76 (s, 3H), 3.74 (t, 2H,
J = 6.6 Hz), 3.41 (t, 2H, J = 6.6 Hz), 2.00 (m, 2H), 1.87 (m, 2H); dC
(CDCl3) 164.7, 136.2, 125.1, 122.5, 121.0, 120.8, 119.7, 119.4, 109.6, 48.3,
45.8, 31.5, 25.9, 24.6; IR n(KBr)/cm21 3456, 2922, 2856, 1733, 1622; m/z
308 (M+), 262, 236, 192 (100%), 158, 129; HRMS: calc. m/z 306.0368,
found m/z 306.0367.
Scheme 5 Reagents and conditions: i, ButLi, THF, BrCl2CCCl2Br, 278 °C
to rt (86%); ii, Bu3SnH, AIBN, toluene, reflux, 48 h (10, 51%; 8, 22%); iii,
ButLi, THF, BrCl2CCCl2Br, 278 °C to rt (90%); iv, Bu3SnH, AIBN,
toluene, reflux, 72 h (13, 51%; 11, 30%); v, ButLi, THF, BrCl2CCCl2Br,
278 °C to rt (94%); vi, Bu3SnH, AIBN, toluene, reflux, 72 h.
1 E. T. Pelkey and G. W. Gribble, Chem. Commun., 1997, 1873; G. W.
Gribble, E. T. Pelkey and F. L. Switzer, Synlett, 1988, 1061; G. W.
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2000, 56, 10133.
tion–translocation of a-amidoyl radical schemes not involving
indoles have been reported.6,11 While we favor the direct
5-endo-trig radical cyclization pathway shown in Scheme 1, of
which there are precedents,12,13 a 4-exo-trig cyclization to a
spiro b-lactam intermediate followed by a 1,2-alkyl migration
(ring expansion), as suggested by a referee, cannot be ruled out.
However, such 1,2-alkyl shifts for radicals are rare14 and the
migration terminus is a nucleophilic carbon-centered radical.
Moreover, based on the work of Ikeda,13 we would have
expected to isolate spiro b-lactams if a 4-exo-trig radical
cyclization pathway was operating.
2 G. W. Gribble, J. Org. Chem., 1972, 37, 1833; G. W. Gribble, J. L.
Johnson and M. G. Saulnier, Heterocycles, 1981, 16, 2109.
3 H. L. Hassinger, R. M. Soll and G. W. Gribble, Tetrahedron Lett., 1998,
39, 3095.
4 J. Bergman and L. Venemalm, J. Org. Chem., 1992, 57, 2495.
5 J. P. Jasinski, J. C. Badenock, H. L. Fraser and G. W. Gribble,
unpublished results.
6 V. Snieckus, J.-C. Cuevas, C. P. Sloan, H. Liu and D. P. Curran, J. Am.
Chem. Soc., 1990, 112, 896.
7 For recent examples, see G. A. Kraus and H. Kim, Synth. Commun.,
1993, 23, 55; S. Caddick, K. Aboutayab, K. Jenkins and R. I. West, J.
Chem. Soc., Perkin Trans. 1, 1996, 675; F. E. Ziegler and M. Belema,
J. Org. Chem., 1997, 62, 1083; C. J. Moody and C. L. Norton, J. Chem.
Soc., Perkin Trans. 1, 1997, 2639; W. Zhang and G. Pugh, Tetrahedron
Lett., 1999, 40, 7591; S.-F. Wang, C.-P. Chuang and W.-H. Lee,
Tetrahedron, 1999, 55, 6109; L. D. Miranda, R. Cruz-Almanza, M.
Pavón, Y. Romero and J. M. Muchowski, Tetrahedron Lett., 2000, 41,
10 181.
8 A. P. Dobbs, K. Jones and K. T. Veal, Tetrahedron, 1998, 54, 2149.
9 A. Fiumana and K. Jones, Tetrahedron Lett., 2000, 41, 4209.
10 S. T. Hilton, T. C. T. Ho, G. Pljevaljcic and K. Jones, Org. Lett., 2000,
2, 2639; S. T. Hilton, T. C. T. Ho, G. Pljevaljcic, M. Schulte and K.
Jones, Chem. Commun., 2001, 209.
11 A. L. J. Beckwith and J. M. D. Storey, J. Chem. Soc., Chem. Commun.,
1995, 977; T. Sato, Y. Kugo, E. Nakaumi, H. Ishibashi and M. Ikeda, J.
Chem. Soc., Perkin Trans. 1, 1995, 1801; M. Ikeda, Y. Kugo and T.
Sato, J. Chem. Soc., Perkin Trans. 1, 1996, 1819; J. Rancourt, V. Gorys
and E. Jolicoeur, Tetrahedron Lett., 1998, 39, 5339; J. M. D. Storey,
Tetrahedron Lett., 2000, 41, 8173.
12 For leading references to 5-endo-trig radical cyclizations, see S. Bogen,
M. Gulea, L. Fensterbank and M. Malacria, J. Org. Chem., 1999, 64,
4920; J. Cassayre, B. Quiclet-Sire, J.-P. Saunier and S. Z. Zard,
Tetrahedron Lett., 1998, 39, 8995.
We thank the National Institutes of Health (GM58601) for
support and Drs Mukund Sibi, Jack Li, and Larry Yet for helpful
discussion.
Notes and references
† Selected physical and spectroscopic data: 4: mp 103–104 0C; dH (300
MHz, CDCl3) 7.59–7.63 (m, 2H), 7.33–7.36 (m, 1H), 6.98–7.13 (m, 2H),
3.78 (s, 3H), 3.53–3.57 (t, 4H, J = 5.4 Hz), 1.38–1.61 (m, 6H); dC (500
MHz, CDCl3, 250 °C ) 166.3, 135.7, 131.6, 125.3, 121.9, 120.4, 120.2,
110.2, 109.7, 48.8, 43.2, 33.3, 26.6, 25.4, 24.4; IR n(KBr)/cm21 2934, 2850,
1611; m/z 242 (M+), 228, 158 (100%), 131, 103, 77 (Calc. for C15H18N2O:
C, 74.35; H, 7.49; N, 11.56. Found: C, 74.23; H, 7.51; N, 11.50%). 5: mp
105–107 °C; dH (300 MHz, CDCl3) 7.46–7.49 (m, 1H), 7.07–7.26 (m, 3H),
3.73 (br s, 5H), 1.59 (m, 8H); dC (500 MHz, CDCl3, 250 °C) 164.5, 135.6,
125.0, 122.1, 120.6, 118.6, 113.9, 110.7, 109.5, 48.2, 42.7, 31.4, 26.6, 25.4,
24.1; IR n(KBr)/cm21 2934, 2845, 1622, 1522, 1428; m/z 320 (M+), 236
(100%), 209, 158, 129; HRMS: calc. m/z 320.0524, found m/z 306.0517. 6:
mp 120–121 °C; dH (300 MHz, CDCl3) 7.40 (d, 1H, J = 7.3 Hz), 7.13 (t,
1H, J = 8.0 Hz), 6.70 (td, 1H, JA = 1.0 Hz, JB = 7.3 Hz), 6.42 (d, 1H, J =
7.7 Hz), 4.14 (dd, 2H, JA = 4.5 Hz, JB = 13.2 Hz), 4.08 (d, 1H, J = 9.4 Hz),
3.84 (dd, 1H, JA = 2.1 Hz, JB = 9.4 Hz), 2.86 (s, 3H), 2.64 (td, 1H, JA = 3.4
Hz, JB = 12.8 Hz), 1.95 (m, 2H), 1.48 (m, 3H); dC (CDCl3) 170.6, 151.0,
128.6, 125.1, 124.9, 118.0, 106.1, 69.2, 62.9, 48.9, 40.6, 33.4, 26.7, 24.6,
23.9; IR n(film)/cm21 2922, 2856, 2344, 1678, 1606, 1489; m/z 242 (M+),
158, 131 (100%), 103, 77; HRMS: calc. m/z 242.1420, found m/z 242.1421;
(Calc. for C15H18N2O: C, 74.34; H, 7.49; N, 11.57. Found: C, 74.12; H,
7.41; N, 11.54%). 8: mp 165–166 °C; dH (300 MHz, CDCl3) 7.68–7.71 (dd,
13 H. Ishibashi, N. Nakamura, K. Ikeda, M. Okada, H. Ishibashi and M.
Ikeda, J. Chem. Soc., Perkin Trans. 1, 1992, 2399; T. Sato, N.
Machigashira, H. Ishibashi and M. Ikeda, Heterocycles, 1992, 33,
139.
14 B. Giese, Radicals in Organic Synthesis: Formation of Carbon–Carbon
Bonds, Pergamon, Oxford, 1986, pp. 19–20; J. Fossey, D. Lefort and J.
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pp. 161–165.
806
Chem. Commun., 2001, 805–806